In many manufacturing processes, and in particular, in the pharmaceutical manufacturing industry, the removal of potentially harmful contaminants from all product contact equipment is of vital importance. It ensures the safety, efficacy and quality of all products that are manufactured using the equipment.
The cleaning procedure utilised in such industries must be validated to verify its effectiveness, based on pre-determined acceptance criteria. Cleaning process validation is thus executed on all product manufacture contact equipment to ensure and verify the removal of all harmful and unwanted contaminants, such as active ingredients, detergents, and microbes, from the equipment prior to its use in another procedure. Cleaning process validation is of the utmost importance, for example, in situations where pharmaceutical process equipment is used for the manufacture of multiple products in succession, for example, as found on a batch manufacture schedule. In this instance, cleaning process validation ensures that there is no cross contamination between individual batches, different products etc., and thus serves to eliminate the risk of the manufacture of contaminated drug products which is wasteful and expensive.
Currently, in the pharmaceutical industry an equipment cleaning process is typically validated by a user swabbing a product contact surface of the equipment after the cleaning process has been completed. The swabs are subsequently analysed by the user, predominantly using HPLC analysis. Significant manufacturing downtime may result, as the manual swabbing procedure and subsequent analytical activity testing may take up to three days to generate approved results, and the equipment cannot be used until approved results are available. As a result, there are several drawbacks and challenges associated with such a cleaning validation process. Trained personnel are required to develop a cleaning validation protocol, as well as to conduct the manual swabbing and the subsequent laboratory analysis. Manual swabbing introduces the risk of human error by way of incomplete or inaccurate sampling of the cleaned surface. The time taken to generate approved results can also have a serious impact on cycle time for the pharmaceutical equipment. There is also the regulatory burden on the user of conducting and maintaining cleaning validation activities on all product contact equipment on site.
There are currently three phases to cleaning procedure implementation, namely, development, validation, and on-going assessment. Cleaning procedure development studies determine cleaning feasibility and investigate whether the cleaning procedure will adequately remove process soils from product-contact equipment surfaces associated with the blending processes. The understanding of soils and the development of cleaning chemistries are fundamental in delivering successful and appropriate cleaning process. The chemistry or agent employed to clean soiled equipment surfaces should be based on the soil characteristics and in-use process parameters. Following development of a cleaning procedure, validation and controls assure that the developed and validated procedure employed is instituted.
As previously stated, cleaning validation is performed to ensure that production materials that come into contact with the blending equipment surfaces, including utensils, are not contaminated or adulterated. A cleaning validation study typically requires a minimum of three consecutive, successful verification runs. In the absence of three batches or other unique circumstances, cleaning verification is performed to ensure the equipment is suitable prior to the next use, however validation using at least 3 consecutive, successful verification runs is eventually necessary. Cleaning validation for cross-contamination relies upon validated analytical methods for the API or selected marker(s). Generally, the core elements of a cleaning validation protocol contains:                A full description of the cleaning process;        The quantities of each material needed;        The exact pieces of equipment and utilities which can be used, confirmation of their respective qualification and calibration statuses;        The recipe (including defined Critical Process Parameters, CPP's);        The sampling plan including directions for swabbing or rinse collection acceptance criteria and justification of same;        Methods of analysis of test results;        References to applicable procedures, policies and guidelines both internal to the organisation and regulatory bodies including what procedure to follow in the event of an out of specification result or a deviation from the protocol;        Roles and responsibilities of all parties involved;        Approval by the Quality Unit.        
The validation process also addresses possible variations in microbiological flora, using a risk-based assessment considering route of administration (i.e. oral, parenteral, topical) and nature of the product. The use profile of the equipment is determined, documented, and categorized into dedicated product/product family equipment or multi-product equipment. Equipment hold times are also considered during a cleaning validation study. Equipment is cleaned as soon as practical after use. Maximum holding times are set between use and cleaning, and cleaning and sampling. The cleaning validation incorporates three runs at the maximum holding time.
The following approaches are typically adopted for multi-product equipment used for manufacturing dosage forms unless special toxicological concerns have been established. The 1/1000 approach may not be suitable for API manufacture, so the 10 ppm approach, or visual determination if that is more conservative, can be substituted.
The 1/1000 Approach:
Not more than 1/1000 of the total minimum daily dose for a 70-kg adult will appear in the maximum daily dose of the next product, except for equipment utilized for paediatric dosage for which a weight adjustment needs to be made accordingly. Refer to the appropriate regulatory guidance for paediatric dosage.                The 10 ppm Approach (Except for Highly Potent Product):        
Not more than 10 ppm of the product being cleaned will appear in the next product.                Visual determination with criteria should also be performed in addition to quantitative methods of analysis.        Highly potent product (special toxicological consideration). The approach shall be individually considered and limits set and justified. Dedicated equipment may be necessary.        
For cleaning agent residue, limits no more than 1/10,000 of the LD50 value for a 70-kg adult appear in the maximum daily dose of the next product for all cleaning agents except for equipment utilized for paediatric dosage for which a weight adjustment needs to be made accordingly. If cleaning development studies demonstrate that water alone is capable of satisfactorily cleaning blending equipment, not only is the cleaning process simplified, but also the validation.
Visual inspection of equipment is performed to align the validation of the cleaning process with the routine inspection of equipment after cleaning. For some products, a visual determination of cleanliness shall be justified when calculations of acceptance criteria for the residual marker(s) is higher than a visual residue determination. This is frequently used for less toxic compounds and especially where an opacifier, such as titanium dioxide, is part of the blend.
At the completion of a validation study, the following activities are in place:                Review of SOPs to assure that they conform to the validated parameters, and inclusion in the equipment status control system.        Recording of routine cleaning operations;        Implementation of change control for the validated equipment and product;        Inclusion in the Validation Master Plan;        Controls over cleaning utensils;        Control over cleaning agents including release by the Quality Unit;        An ongoing monitoring program of the effectiveness of the cleaning program shall be considered, including periodic verification studies. Special consideration shall be given to highly potent products and microbial cleanliness after storage. Alternately, a means of continuous monitoring, such as PAT, may be employed. Frequently, the final rinsate is tested for conductivity/resistance to determine if the blending equipment cleaning was satisfactory. The level and sensitivity of the testing of final rinsate may depend upon the quality of the water used for that final rinse.        
The above outlined current approach to cleaning procedure development and validation is a time consuming and costly process that significantly inhibits clinical trial manufacture activities (because of once-off swabbing requirements following each mini-batch manufactured) and on-going commercial manufacturing activities (because of the burden associated with cleaning procedure validation).
The use of visual inspection as an assessment criterion for equipment cleaning effectiveness has always been a component of cleaning programs. Mendenhall proposed the use of only visual examination to assess equipment cleanliness in 19893. He summarised that visible cleanliness criteria were more rigid than quantitative calculations and therefore adequate. The US food and Drug Administration acknowledges the use of visually clean criteria for product dedicated equipment. LeBlanc has also reviewed the use of visual examination as the sole acceptance criteria for cleaning validation4.
A Visible-residue Limit (VRL) is the quantity of marker (usually API) remaining on manufacturing equipment surfaces when it has reached a visually detectable level. An Acceptable-residue Level (ARL) is the amount of marker (usually API) that can remain on manufacturing equipment surfaces and carry over to the next formulation with no pharmacological or adulteration risk. Forsyth et al5 propose that VRL's could be adopted as the primary acceptance criteria during cleaning evaluation activities if the VRL is calculated to be less than the ARL. They cited the following advantages of a properly validated and maintained VRL program:                VRL involves testing all visible equipment surfaces—not just swabbed areas during routine validation activities;        VRL inspections reduce the personnel time needed to swab the manufacturing equipment;        They eliminate ongoing analytical resources beyond the initial validation;        Method development and validation resources for new development compounds are not required;        With the expanded use of VRL data in lieu of surface testing, the extent of testing and documentation necessary for each assessment is reduced, as well as the cost for long-term storage of the documentation and data;        The manufacturing team have instant availability of visual-testing results, which minimises equipment down-time while waiting for analytical results, therefore increasing manufacturing productivity.        
Forsyth et al identified the following risks and limitations when using VRL's                The potential that dirty equipment passes visual inspection and the subsequent manufactured formulation is adulterated. It was acknowledged that the closer the VRL is to the ARL, the greater the risk becomes;        To date, VRL determinations have been limited to stainless steel surfaces. The consistency of VRL assessments from transparent equipment materials may be considerably more challenging;        VRL approaches also have limitations with respect to assessing microbiological control;        The subjectivity of observers and the variability of interpretation of ‘visually clean’ is also identified as a risk of using ARL's6;        The impact of environmental factors (especially light levels) may also impact the individual interpretation of ‘visually clean’ criteria. This is particularly a challenge with large scale manufacturing equipment;        The limitation of such an approach to low potency API's where the ARL's are sufficiently high to be greater than the VRL's.        
Within the FDA draft guidance document on Process Validation, it is defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products. Process validation involves a series of activities taking place over the lifecycle of the product and process. This guidance describes the process validation activities in three stages.
Stage 1—Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale-up activities.
Stage 2—Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing.
Stage 3—Continued Process Verification: Ongoing assurance is gained during routine production activities that the process remains in a state of control.
However there vulnerabilities associated with such an approach, in particular the person-to-person variability of ‘visually clean’ equipment and the lighting challenges associated with commercial scale equipment. Even with considerable training and experience these risks may remain.
Some examples of alternative technologies currently used to continuously verify equipment cleaning process are as follows:
Lab Based Technologies:
Ion Mobility Spectrometry
Ion mobility spectrometry is a type of separation technique, similar to time of flight mass spectrometry, that distinguishes ions of a given compound based on their velocities through a drift tube under the influence of a weak electric field. It is a fast and specific off-line tool for verifying the cleanliness of pharmaceutical equipment. Recovery percentages and standard deviations for IMS samples are consistent with those obtained with HPLC analysis, but sample throughput of IMS is about 50 times faster7. The disadvantages associated with such a method are that it is an off-line analytical tool that requires sample swabbing and preparation activities.
LC-MS-MS
For low-dose compounds, equipment requiring low residue limits, and compounds lacking strong chromophores, the enhanced sensitivity and selectivity of liquid chromatography-mass spectrometry-mass spectrometry (LC-MS-MS) facilitates rapid method development for the detection of low levels of residues of active pharmaceutical ingredients8. Like Ion Mobility Spectrometry, the disadvantages associated with LC-MS-MS are that it is an off-line analytical tool that requires sample swabbing and preparation activities.
At-Line Technologies:
ATP Luminescence
ATP luminescence-based technologies may be used to evaluate the level of microbial contamination following the completion of an equipment cleaning process. This is a rapid method of swab analysis that is an accepted method within the food and beverage industries.
On-line Technologies:
UV-Vis Spectrophotometry
UV-Vis technologies monitor rinse effluent to quantify the level of API remaining. When the level of API in the rinse effluent reaches an acceptable level the cleaning process end-point is reached. This is a novel approach that has significant benefits for identification of cleaning process endpoint. One disadvantage identified may be associated with the non-detection of API if it is adhered to the vessel wall following prolonged dirty hold-time studies.
TOC
TOC is a technology that may have potential for monitoring of rinse effluent following an equipment cleaning process in particular for detergents. It has excellent sensitivity capability however the method is non-specific and is also limited as the potential contamination remaining on the equipment surface, if remaining, will not be detected.
Single Point NIR
Portable single point Mid IR systems have been developed for real-time, in-situ surface analysis using grazing-angle infrared spectroscopy. Organic films and coatings on metal and glass surfaces can be measured and identified in seconds9. The system was originally developed for use in the aerospace industry. Single point NIR technology does not however generate an image of the sample area or provide a calculation of the concentration of target residue remaining on the surface.
U.S. Pat. No. 7,557,923 relates to multipoint analysis of the presence or concentration of an analyte on a surface using a single point NW system. Point-source spectroscopic assessments do not provide information on spatial distribution of different constituents. In other words, NIR and Raman spectroscopy can only provide information on a very narrow sample site and so do not lend themselves to quantifying over a given area at a single point in time.
Chemical Imaging (CI) is an emerging platform technology that integrates conventional imaging and spectroscopy to attain both spatial and spectral information from an object. Near infrared-chemical imaging (NIR-CI) is the fusion of near-infrared spectroscopy and image analysis. NIR Chemical Imaging has been used for purposes within pharmaceutical manufacturing for the assessment of homogeneity of blended materials and tablets. It can be used to visualize the spatial distribution of the chemical compounds in a sample, providing a chemical image. Each sample measurement generates a hyperspectral data cube containing thousands of spectra. An important part of a NIR-CI analysis is the data processing of the hyperspectral data cube.
By combining the chemical selectivity of vibrational spectroscopy with the power of image visualisation, Chemical Imaging enables a more complete description of the sample. The large number of individual spectra acquired across the spatial dimension of heterogeneous compounds provides a basis from which relative concentrations can be determined for each spatial location. Alternatively, these individual concentrations may be added together to give the total concentration of a specific material within the sample area.
Chemical Images are made up of hundreds of contiguous wavebands for each spatial position of a target studied. Consequently, each pixel in Chemical Image contains the spectrum of that specific position. The resulting spectrum acts like a fingerprint, which can be used to characterise the composition of that particular pixel. There are two basic methods to construct the chemical image. On method involves acquisition of simultaneous spectral positions. The object is moved underneath an imaging spectrograph—this is termed pushbroom acquisition. The other method involves keeping the image field of view fixed and obtaining images one wavelength after another—this is termed staring imager configuration11.